Pharmaceutical composition containing fara-amino-benzoic acid-N-D-xyloside as an active ingredient

ABSTRACT

Disclosed is a pharmaceutical composition containing p-aminobenzoic acid-N-D-xyloside or a pharmaceutically acceptable salt thereof as an active ingredient.

CROSS-REFERENCES TO RELATED APPLICATION

This application is a continuation-in-part of our copending application,Serial No. 39282 filed May 15, 1979, and now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to a pharmaceutical composition containinga compound represented by the following general formula: ##STR1##wherein ¹ R denotes the residual group formed by removing the OH groupof 1 position from xylose, or its pharmaceutically acceptable saltselected from the group consisting of its Na, K, Mg, Ca and Al salts.

The inventors of the present invention, during the course of searchingchemical compounds having antitumor activity, have found that chemicalcompounds represented by the abovementioned formula (1) have a number ofphysiological activities such as blood sugar-reducing activity,antihypertensive activity, blood lipid-reducing activity,antiinflammatory activity and central nerve-depressing activity inaddition to its antitumor activity.

Although the above-mentioned aminobenzoic acid derivatives are knowncompounds, no report has been found on the physiological activity of thecompounds.

"Inoue, et al. N-Glycosides. XIX. Preparation of anthranilic acidN-glycosides., Chemical Abstracts, Vol. 48 (1954), Column 2001 i." and"Inoue, et al. N-Glycosides. XXV. Paper chromatography of N-glycosides.,Chemical Abstracts, Vol. 48 (1954), Column 2003 a." disclose thechemical syntheses of the compounds which are the active ingredients ofthe pharmaceutical composition of the present invention. However, thereis no utility disclosed in this prior arts and no teaching ofpharmaceutical "dosage unit forms".

Furthermore, although U.S. Pat. No. 2,659,689 discloses a p-aldiminobenzoic ester and a composition for protecting the human skin fromerythema producing rals, the composition comprising a solution ofp-aldimino benzoic ester, there is no teaching of pharmaceutical "dosageunit forms".

SUMMARY OF THE INVENTION

In an aspect of the invention, there is provided a pharmaceuticalcomposition having effectiveness in antitumor activity, bloodsugar-reducing activity, antihypertensive activity, blood lipid-reducingactivity, antiinflammatory activity and central nerve-depressingactivity, based on the discovery of the new medical use of the chemicalcompounds represented by the following formula (1).

BRIEF DESCRIPTION OF THE DRAWING

The annexed FIGS. 1 to 2 show respectively the infrared absorptionspectra of respective compound No. 1 to No. 2 in Table 1.

DETAILED DESCRIPTION OF THE INVENTION

The active ingredient of the pharmaceutical composition of the presentinvention is a compound represented by the following formula: ##STR2##wherein ¹ R is as described above, or its pharmaceutically acceptablesalt selected from the group consisting of its Na, K, Mg, Ca and Alsalts. The sugar moiety of the active ingredient has a structure of apyranose ring.

The method of preparation of the active ingredient of the presentinvention is illustrated as follows:

A mixture of 4.5 to 5 g of p-aminobenzoic acid, 5-6 g of D-xylose and0.1 to 0.5 g of ammonium chloride was heated in 40 to 90 ml of 95 to100% ethanol or pure methanol under a reflux condenser to inducecondensation. After the reaction is over, the reactant is left at roomtemperature or in a cool place and the crystals separated out arecollected by filtering the reactant solution. These crystals were washedwith water, ethanol or ethyl ether, and then recrystallized from anaqueous solution of methanol or ethanol.

In order to substitute the hydrogen atom of the carboxyl group of thethus prepared compound with a base, it is preferable to follow the knownmethod. The compound, paraaminobenzoic acid-N-D-xyloside, is dissolvedin an aqueous ethanolic solution and an inorganic salt is added to thesolution to effect the substitution.

The physical properties of the compounds (the active ingredient of thepharmaceutical composition of the present invention) prepared by theabove-mentioned methods are shown in Table 1, and their infraredabsorption spectra are respectively shown in FIGS. 1 to 2. Methods ofdetermination of the physical properties are as follows.

                                      TABLE 1                                     __________________________________________________________________________    Physical Properties of the Active Ingredients                                                 Specific        Ultraviolet                                              Melting                                                                            rotation                                                                              Elementary                                                                            absorption                                               point        analysis (%)                                                                          Maximum                                       Compound   (° C.)                                                                      [α] .sub.D.sup.D.sup.20                                                         C : H : N                                                                             (millimicron)                                 __________________________________________________________________________      p-aminobenzoic                                                                         172  +61.6   53.4 : 5.6 : 5.2                                                                      287                                             acid-N-D-xyloside                                                                           in 94% ethanol                                                                        (53.5 : 5.6 : 5.2)                                      Sodium p-amino-                                                                        149-158                                                                            0       49.3 : 4.9 : 4.8                                                                      274                                             benzoate-N-D- in water                                                                              (49.5 : 4.8 : 4.8)                                      xyloside                                                                    __________________________________________________________________________      Note:                                                                        (: : ) = theoretical values of C, H and N (%).                           

(1) Melting point: determined by the use of micro melting pointdetermination apparatus made by Yanagimoto Works, Japan.

(2) Specific rotation: determined by using direct-reading polarimeterModel OR-50 made by Yanagimoto Works, Japan, with a thickness of 50 mmof an aqueous ethanolic solution of the acidic active ingredient and anaqueous solution of the sodium salt of the acidic active ingredient.

(3) Molecular composition: Elementary analysis was carried out by usingOHN-Coder Model MT-2 made by Yanagimoto Works, Japan.

(4) Ultraviolet absorption spectrum: by using self-recordingspectrophotometer Model PS-3T made by Hitachi Works, Japan, on anaqueous ethanolic solution of the acidic active ingredient and on anaqueous solution of the sodium salt of the acidic active ingredient.

(5) Infrared absorption spectrum: determined by KBr-method usinginfrared absorption spectrometer Model DS-701G made by Nippon Bunko Co.,Ltd., Japan. The chart number of the spectrogram coincides with thenumber of specimens of the active ingredient.

The followings are the physiological properties of the active ingredientof the pharmaceutical composition of the present invention described inthe order of (1) acute toxicity, (2) antimicrobial activity, (3)mutagenicity, (4) delayed-type intracutaneous reaction and (5)antibody-producing activity.

(1) Acute toxicity

Acute toxicity of the active ingredient was examined by respectiveintraperitoneal and oral (forcible) administration to ICR-JCL mice. Thespecimen was dissolved in the physiological saline solution inintraperitoneal administration, and dissolved in distilled water in oraladministration.

Their symptoms were observed after administration until the 7th day ofadministration, and LD₅₀ of the specimen was obtained from the mortalityaccumulated to the 7th day, according to the graphic method ofLitchfield-Wilcoxon. The results are shown in Table 2. As is seen inTable 2, LD₅₀ of the specimen is larger than 11 g/kg, regardless of theroutes of administration, and shows that the active ingredient of thepresent pharmaceutical composition is an ordinary medicine with lowtoxicity, to be highly safe.

                  TABLE 2                                                         ______________________________________                                        Acute toxicity of the active ingredient (LD.sub.50 in g/kg)                                      Route of administration                                    Compound             Intraperitoneal                                                                           Oral                                         ______________________________________                                        Sodium p-aminobenzoate-N-D-xyloside                                                                11.04       11.75                                        ______________________________________                                    

(2) Antimicrobial activity

The active ingredient was dissolved in distilled water at a series oftwo fold dilution system. These diluted solutions were mixed with agarmedium in 9 times by volume, and the mixture was poured into a petridish. Heart infusion agar medium was used for bacteria, and Sabouraud'sagar medium was used for fungi. After streaking with the pre-culture,the inoculated plates were incubated at 37° C. for 20 to 24 hours forbacteria and at 25° C. for 3 to 7 days for fungi, and then the growthwas examined. The following microorganisms were used for assessing theantimicrobial activity:

Pseudomonas aeruginosa IAM 1514

Escherchia coli IFO 12734

Staphylococcus aureus 209 P

Bacillus subtilis IAM 1069

Saccharomyces cerevisiae IAM 4207

Candida albicans ATCC 752

Trichophyton mentagrophytes IFO 6124

Aspergillus niger IAM 3001

As the result of the above-mentioned tests, it was found that the activeingredient did not show any growth inhibition against all themicroorganisms at a concentration of 1 mg/ml.

(3) Mutagenicity

As the first stage, the active ingredient was tested by rec-assay (i),and the second stage, it was tested by reversion assay (ii).

(i) A strain of Bacillus subtilis M 45, a defectant of recombinationrepair, and another strain of Bacillus subtilis H 17 keepingrecombination repair activity were inoculated to make their own streaksnot crossed at the start on B-2 agar culture plate (made by dissolving10 g of the meat extract, 10 g of polypeptone, 5 g of sodium chlorideand 15 g of agar in 1000 ml of distilled water at a pH of 7.0).

Then, a circular sheet of filter paper 8 mm in diameter, which absorbed0.04 ml of an aqueous solution of the active ingredient (usingsterilized water) was put on the surface of the agar plate so as tocover the starting point of the abovementioned streaks of bacterialculture. The inoculated B-2 agar culture was kept at 37° C. for a nightand the length of growth-inhibited region was measured. Kanamycin wasused as the negative control and Mitomycin C was used as the positivecontrol. The results of the rec-assay are shown in Table 3.

(ii) The strains TA 98 and TA 100 (both are histidine requiring) ofSalmonella typhimurium were used in the reversion assay.

Into 2 ml of a soft agar culture medium (the medium itself contains 6 gof sodium chloride and 6 g of agar in 1000 ml of distilled water) towhich one tenth by volume of an aqueous solution of 0.5 mM of biotin and0.5 mM of histidine, 0.1 ml of the bacterial suspension and 0.1 ml of anaqueous solution of the active ingredient were admixed and the mixturewas layered on the minimum agar culture medium. After 2 days ofincubation at 37° C., the number of revertant colonies was counted.

Furylfuramide (AF-2) was used as the positive control. The results ofthe reversion assay are shown in Table 4.

As is seen in Table 3, the active ingredient showed no mutagenicity evenat a high concentration of 5000 microgram/disk. And as is seen in Table4, the rate of occurrence of mutation by the active ingredient of thepharmaceutical composition of the present invention did not show anydifference from that in the control to which no substance was added,even at a high concentration of 5000 microgram/plate. These findingsdemonstrate that the active ingredient is safe in view of mutagenicity.

                  TABLE 3                                                         ______________________________________                                        Result of rec-assay                                                                            Length of                                                                     growth-inhibition zone                                                  Concentration                                                                             M 45    H 17  *Difference                              Compound   (μg/plate)                                                                             (mm)    (mm)  (mm)                                     ______________________________________                                        Sodium p-amino-                                                                          500         0       0     0                                        benzoate-N-D-                                                                 xyloside   5000        0       0     0                                        Kanamycin  10          5       4     1                                        Mitomycin C                                                                              0.05        12      2     10                                       ______________________________________                                         Note:-                                                                        *Difference = length of inhibition zone of M 45 minus length of inhibitio     zone of H 17.                                                            

                  TABLE 4                                                         ______________________________________                                        Result of reversion assay test                                                                        Number of                                                                     revertant colonies                                                 Concentration                                                                            (n/plate)                                             Compound       (μg/plate)                                                                              TA 100  TA 98                                     ______________________________________                                        Sodium p-aminobenzoate-                                                                      5000          58      4                                        N-D-xyloside                                                                  Furylfuramide   0.1         911     167                                       Control (nothing added)                                                                      --           149      13                                       ______________________________________                                    

(4) Delayed-type intracutaneous reaction

In order to know the effects of the active ingredient on cellularimmunity, the foot pad reaction test was carried out using ICR-JCL miceas experimental animals and erythrocytes of sheep as an antigen.

A mouse was primary-sensitized by injecting 0.2 ml of 10% suspension ofsheep erythrocytes in physiological saline solution from the caudal veinand after 7 days of the first sensitization, 0.05 ml of 40% suspensionof sheet's erythrocytes in physiological saline solution was injected inthe foot pad for the second sensitization. The thickness of the foot padwas determined on the next day. The administration of the activeingredient of the medicine of the present invention as carried out atthe dosage of 250 mg/kg/day once a day for consecutive 5 days centeringaround the day when the first sensitization was carried out.

As the result, the increment of the thickness of the foot pad of themouse administered with the active ingredient showed no significantdifference as compared to the increment in the group of mouse notadministered with the active ingredient.

(5) Antibody-producing activity

In order to know the effects of the active ingredient on humoralimmunity, the hemagglutination test was carried out using ICR-JCL micesensitized with sheep erythrocytes.

A mouse was sensitized by injecting 0.2 ml of 10% suspension of sheeperythrocytes in physiological saline solution from the caudal vein andafter 7 days of sensitization the mouse blood was sampled for thehemagglutination test of determination of the antibody-producingactivity. The active ingredient was administered for consecutive 5 dayscentering around the day of sensitization, intraperitoneally at thedosage of 250 mg/kg/day.

As the result, there was no significant difference in agglutinationtiter between the group administered with the active ingredient and thecontrol group.

The followings are the pharmacological properties of the activeingredient of the pharmaceutical composition of the present inventiondescribed in the order of (1) blood sugar-reducing activity, (2)antihypertensive activity, (3) antitumour activity, (4) analgeticactivity, (5) antipyretic activity, (6) antiinframmatory activity and(7) blood lipid reducing activity.

(1) Blood sugar reducing activity

Streptozotocin was administered intraperitoneally to a group of Wistarrats at a dosage of 60 mg/kg and after confirming the positivity ofurinary sugar of the animals on the 8th day, regular insulin was furtheradministered to the rats to reduce both the urinary sugar and the bloodsugar. Out of thus treated animals, those which certainly showed ahigher uninary sugar value and also a higher blood sugar value (meanvalue of 500 mg/dl) after a few days of insulin-administration were usedas the model animals suffering from artificial diabetes mellitus. Theactive ingredient was administered to the model animals orally as asolution in distilled water at the respective dosages of 30 and 300mg/kg. Blood specimens after 3 and 6 hours of the administration, andthe determination of glucose in the specimen was carried out by using aRaBA-kit (made by Chugai Pharmaceutical Co., Japan) according to theenzyme method.

The results are shown in Table 5. As is seen in Table 5, the differencebetween the values (Δ value) of blood sugar before and after theadministration of the active ingredient was larger than the Δ value ofcontrol which were given only distilled water.

                  TABLE 5                                                         ______________________________________                                        Blood sugar-reducing activity                                                                     Change (Δvalue, mg/dl)                                           Dose   of blood sugar after                                      Compound       (mg/kg)  3 hrs.    6 hrs.                                      ______________________________________                                        Sodium p-aminobenzoate-                                                                       30      -105      -110                                        N-D-xyloside   300      -58       -63                                         Control        --       -36       -39                                         ______________________________________                                    

(2) Antihypertensive activity

An aqueous solution of the active ingredient in distilled water wasorally administered to rats of spontaneous hypertension at respectivedosages of 30 and 300 mg/kg and their blood pressure was determinedafter 3 and 6 hours of administration by a sphygmomanometer (made byUeda Works, Japan, Model USM-105R). The difference of blood pressuresbefore and after the administration was used to evaluate theantihypertensive activity of the active ingredient. Mean value of bloodpressure of the above-mentioned rats in spontaneous hypertension was 200mmHg.

The results are shown in Table 6. As is seen in Table 6, the activeingredient clearly showed the antihypertensive effect.

                  TABLE 6                                                         ______________________________________                                        Antihypertensive activity                                                                         Reduced amount of blood                                                Dose   pressure after                                                         rate   3 hrs.    6 hrs.                                          Compound       (mg/kg)  (mmHg)                                                ______________________________________                                        Sodium p-aminobenzoate-                                                                       30      32        35                                          N-D-xyloside   300      26        25                                          Control        --       -2*        2                                          ______________________________________                                         Note:-                                                                        *Blood pressure was raised by 2 mmHg.                                    

(3) Antitumour activity

Sarcoma-180 were transplanted subcutaneously into the right axillary ofICR-JCL mice at the rate of 1×10⁶ cells/mouse, and from after 24 hoursof transplantation an aqueous solution of the active ingredient insterilized physiological saline solution was orally administered everyother day at a dose rate of 500 mg/kg, 10 times in all. On the 25th dayof the transplantation, the nodular tumour(s) was extirpated andweighed.

The inhibition rate (I.R.) (%) of the active ingredient was calculatedby the following formula:

    (1-T/C)×100=I.R. (%)

wherein

T: mean weight of the tumour(s) in treated group of mice

C: mean weight of the tumour(s) in control group* of mice

The result of the test is shown in Table 7. As is seen in Table 7, theactive ingredient exhibited an antitumour activity.

                  TABLE 7                                                         ______________________________________                                        Antitumour activity against Sarcoma-180                                                             Inhibition ratio                                        Compound              (I.R.%)                                                 ______________________________________                                        Sodium p-aminobenzoate-N-D-xyloside                                                                 54.7                                                    ______________________________________                                         Note:-                                                                        Amount of administration was 10 × 500 mg/kg p.o.                   

(4) Analgetic activity

Determination by the mechanical stimulation method (by applyingpressure)

Female ICR mice which showed a threshold value of pain of 50 to 80 mmHgwhen their tail base part was pressed by a pressure stimulationapparatus (made by Natsume Works, Japan) of Takagi and Kameyama werechosen as test animals, ten animals comprising a group.

After administering the active ingredient, the test was carried out asthe time passes and the applied pressure and the time period until theanimal showed a quasi-escaping reaction were determined to evaluate theanalgetic activity of the active ingredient.

The result is shown in Table 8. As is seen in Table 8, the pressureapplied on animals when the animal showed the quasi-escaping reactionwas higher in animals to which the active ingredient has been appliedthan in animals not administered, and the time period from the beginningto the time point when the animal showed the reaction was longer inanimals administered with the active ingredient than in animals notadministered. Thus, the analgetic activity of the active ingredient wasconfirmed.

Determination by the chemical stimulation method

The active ingredient was orally administered to a group (ten animals)of female ICR mice of age of 5 to 6 weeks, and after 30 min of theadministration an aqueous 0.6% acetic acid solution wasintraperitoneally injected into the mouse at a dose rate of 0.1 ml/10 gof body weight. The number of writhing syndrome which occurred in themouse during 10 minutes after 10 minutes of intraperitonealadministration was recorded. The analgetic activity was evaluated fromthe writhing syndrome-inhibiting ratio obtained by the followingformula:

    (1-T/C)×100=writhing syndrome-inhibiting ratio (%)

wherein

T: mean number of writhing syndrome in the group administered

C: mean number of writhing syndrome in the control group.

The result is shown in Table 9. As is seen in Table 9, the activeingredient of the pharmaceutical composition of the present inventionshowed analgetic activity. The above-mentioned process was carried outfollowing the method of Kostet et al. (1959).

                  TABLE 8                                                         ______________________________________                                        Analgetic activity by the mechanical stimulation method                                          Quasi-escape reaction                                                         pressure at time until                                                        (mmHg)  (sec.)                                             Compound             occurrence                                               ______________________________________                                        Sodium p-aminobenzoate-N-D-xyloside                                                                106       47                                             Control               70       33                                             ______________________________________                                         Note:-                                                                        Amount of administration, 1000 mg/kg p.o.                                

                  TABLE 9                                                         ______________________________________                                        Analgetic activity by the chemical stimulation method                         Compound               I.R. (%)                                               ______________________________________                                        Sodium p-aminobenzoate-N-D-xyloside                                                                  48.1                                                   ______________________________________                                         Note:-                                                                        Amount of administration was 1000 mg/kg p.o.                             

(5) Antipyretic activity

Following the method of Winter et al. (1961), a 20% suspension of beeryeast was subcutaneously injected to a group (consisting of 6 animals)of rats, and after 10 hours of fasting, the active ingredient was orallyadministered to the rats and their rectal temperature was determined.

The antipyretic activity is expressed by the ratio of inhibiting pyrexiadue to beer yeast (I.R. %) at the time when the antipyretic activity ofthe active ingredient is at its maximum according to the followingformula: ##EQU1## wherein T: mean rectal temperature of rats to whichthe active ingredient was administered.

C₁ : mean rectal temperature of rats injected beer yeast, without theactive ingredient.

C₂ : mean rectal temperature of untreated rats (control).

The result is shown in Table 10. As is seen in Table 10, the activeingredient exhibited a considerable antipyretic activity.

                  TABLE 10                                                        ______________________________________                                        Antipyretic activity                                                                             Antipyretic activity                                                          (suppressing pyrexia)                                      Compound             I.R. (%)                                                 ______________________________________                                        Sodium p-aminobenzoate-N-D-xyloside                                                                70.0                                                     ______________________________________                                    

(6) Antiinflammatory activity

(a) Carrageenin-edema inhibitory activity

Following the method of Van Arman et al. (1963), the active ingredientwas forcibly and orally administered to each rat of a group consistingof 10 animals at the dose rate of 1000 mg/kg, and after one hour of theadministration 0.1 ml of 1% suspension of carrageenin in physiologicalsaline solution was injected to their right foot pad. The volume of thefoot pad was determined as time passes and the antiinflammatory activitywas expressed by the ratio of inhibition of the swelling of the foot paddue to the carrageenin by the active ingredient, using the maximumdetermined value during 1 to 4 hours after the injection, andcalculating by the following formula:

    (1-T/C)×100=I.R.(%)=antiinflammatory activity

wherein

T: mean value of volumes of foot pad in administered animals.

C: mean value of volume of the foot pad of control (not administered andthen injected).

The result is shown in Table 11. As is seen in Table 11, the ingredientshowed the inhibitory activity against the edema caused by carrageenin.

(b) Antigranuloma activity

Following the method of Winter et al. (1963), two cotton wool pelletswere implanted into the skin of back of each rat of a group consistingof 6 rats at the symmetrical positions having the median line as theaxis of symmetry, the weight of one pellet being 30±1 mg. Oraladministration of 1000 mg/kg/day of the active ingredient was carriedout for consecutive 7 days. On the 8th day, the granuloma formed in therats was extirpated and weighed after drying. The antigranuloma activityexpressed by the ratio of inhibition of the growth of the granuloma(I.R.%) was calculated in a manner as shown in (6) (a), and the resultis shown in Table 11. As is seen in Table 11, the active ingredientexhibited the inhibiting activity of growth of the granuloma.

(c) Antiexudation activity

Following the method of Baris et al. (1965), a volume of air wasinjected subcutaneously in the back of each rat of a group consisting of6 rats to make an air pouch, and then 0.5 ml of 1% croton oil solutionin sesame oil was injected into the pouch. The oral administration of1000 mg/kg/day of the active ingredient was then begun to continue for 5days. On the 6th day, the amount of exudated liquid into the pouch wasdetermined and the anti-exudation activity expressed by the ratio ofinhibitory activity to exudation was calculated in a manner as shown in(6) (a). The result is shown in Table 11. As is seen in Table 11, theactive ingredient exhibited the anti-exudation activity.

(d) Antiadjuvant-arthritis activity

Following the method of Fujiwara et al. (1971), Mycrobacteriumtuberculosis suspended in liquid paraffin was injected subcutaneouslyinto the right foot pad of each rat of a group consisting of 6 rats.After 14 days of the injection, rats with similar volume of the foot padwere chosen to form groups (10 animals/group), the active ingredient wasorally administered daily from the 15th day of consecutive 7 days at thedose rate of 1000 mg/kg/day. The volume of the foot pad of rats wasdetermined, and the antiadjuvant arthritis activity of the activeingredient was calculated as the ratio of inhibiting the swelling of thefoot pad by using the formula shown in (6) (a). The result is shown inTable 11. As is seen in Table 11, the active ingredient exhibited theantiadjuvant arthritis activity.

                  TABLE 11                                                        ______________________________________                                        Antiinflammatory activity                                                     Compound    Edema   Granuloma Exudation                                                                             Arthritis                               ______________________________________                                        Sodium p-amino-                                                                           50.6    13.2      39.7    41.3                                    benzoate-N-D-                                                                 xyloside                                                                      ______________________________________                                         Note:-                                                                        Amount of administration of the active ingredient = 1000 mg/kg/day       

(7) Blood lipid reducing activity

Japanese male white rabbits were fed for about 3 months with solid feed(CR-1) containing 1% of cholesterol and those animals in which theincrease of seral lipid component was confirmed were used as the modelanimals having experimental arteriosclerosis.

An aqueous solution of the active ingredient in distilled water wasadministered respectively at the dose rates of 30 and 300 mg/kg orallyand after the administration, blood specimen was collected as timepasses from the auricular vein and the change of total cholesterol(determined by the enzyme method), phospholipid (determined by theenzyme method) and beta-lipoprotein (determined by turbidmetry) in theserum was observed.

The results are shown in Table 12. In Table 12, the values of serumcholesterol (mean value of 550 mg/dl), of serum phospholipid (mean valueof 320 mg/dl) and of serum beta-lipoprotein (mean value of 2500 mg/kg)before administration were respectively subtracted from the respectivevalues after 3 and 6 hours of the administration, and only thedifferences are shown, respectively. Therefore, the minus value showsthe decrease and the plus value shows the increase of the respectivevalues due to the administration. As is clearly seen in Table 12, theactive ingredient exhibited an activity of reducing the lipid componentsof serum as compared to control.

                                      TABLE 12                                    __________________________________________________________________________    Activity of reducing blood lipids                                                           Phospholipid                                                                          beta-Lipoprotein                                                                       Cholesterol                                                  (mg/dl) (mg/dl)  (mg/dl)                                                 Dose                                                                 Compound (mg/kg)                                                                            3 hrs.                                                                            6 hrs.                                                                            3 hrs.                                                                            6 hrs.                                                                             3 hrs.                                                                             6 hrs.                                    __________________________________________________________________________    Sodium p-amino-                                                                         30  -33 -114                                                                              -143                                                                              -126 -75  -25                                       benzoate-N-D-                                                                 xyloside 300  -56 -73 -189                                                                              -167 -150 -50                                       Control  --   0   -19 0   +3   +8   -4                                        __________________________________________________________________________

Now, the formulation of the active ingredient to make the pharmaceuticalcomposition of the present invention is described below.

In the case where the pharmaceutical composition is used as anantiinflammatory agent, it is able to use the pharmaceutical compositionin the form which is convenient to obtain the effectiveness according tothe kinds and the symptoms of the disease, and moreover, the activeingredient may be used as itself or may be used as mixtures combinedwith any diluent allowable in pharmaceutical process and with othermedicines.

The pharmaceutical composition of the present invention is administeredorally or parenterally and accordingly, the pharmaceutical compositionof the present invention may take any form optionally for the oral orparenteral administration.

The pharmaceutical composition of the present invention may be offeredas a form of unit administration. The form of the pharmaceuticalcomposition of the present invention may be powder, granule, tablet,sugar-coated tablet, capsulated one, suppository, suspension, solution,emulsifiable concentrate, ampouled one, injection, etc. As a diluent,any one of solids, liquids and semisolids may be utilized, for instance,excipients, binders, wetting agents, disintegrating agents, surfactants,demulcents, dispersing agents, buffering agents, perfumes,preservatives, dissolution aids and solvents. Moreover, one or more thanone of these adjuvants may be used in combination or in mixtures.

The pharmaceutical composition of the present invention may beformulated by any known method, and the amount of the active ingredientcontained in the composition (preparation) is generally from 0.01% to100% by weight.

The pharmaceutical composition of the present invention may beadministered orally or parenterally to human or animals, however, it ispreferably administered orally. Sublingual administration is included inoral administration. Parenteral administration includes subcutaneous-,intramuscular- and intravenous injection and the injection by dropmethod.

The dose of the pharmaceutical composition of the present inventiondepends upon the age, the personal difference and the state of disease,and whether the object is human or animal and accordingly, anextraordinal amount may be administered than the following dose:Generally, for human, the oral dose is 0.1-1000 mg/kg body weight/day,preferably 1-500 mg/kg/day and the parenteral dose is 0.01-200mg/kg/day, preferably 0.1-100 mg/kg/day divided into 1-4 parts, one partbeing administered in one time.

The followings are the more detailed explanation of the formulation andthe production of the pharmaceutical composition of the presentinvention in examples.

EXAMPLE 1 (Formulation)

10 parts by weight of sodium p-aminobenzoate-N-D-xyloside,

15 parts by weight of (heavy) magnesium oxide and

75 parts by weight of lactose were uniformly mixed

and formulated into powder or granules. The powder is filled in capsulesto be capsulated-formulation.

EXAMPLE 2 (Formulation)

45 parts by weight of sodium p-aminobenzoate-N-D-xyloside,

15 parts by weight of starch,

16 parts by weight of lactose,

21 parts by weight of crystalline cellulose,

3 parts by weight of polyvinyl alcohol and

30 parts by weight of water were uniformly mixed,

crushed and formulated, and then dried and shifted to be granules.

EXAMPLE 3 (Formulation)

Granules were prepared as in Example 2, and the mixture of 96 parts byweight of this granule and 4 parts by weight of calcium stearate wascompression-formulated to be tablets 10 mm in diameter.

EXAMPLE 4 (Formulation)

94 parts by weight of sodium p-aminobenzoate-N-D-xyloside,

6 parts by weight of polyvinyl alcohol and

30 parts by weight of water were mixed and the mixture

was processed as in Example 2 to be granules. To 90 parts by weight ofthe thus processed granules 10 parts by weight of crystalline cellulosewere mixed and the mixture was compression-formulated to be tablets 8 mmin diameter. The tablets were coated with syrup, gelatine andprecipitated calcium carbonate to be coated tablets.

EXAMPLE 5 (Formulation)

0.6 parts by weight of sodium p-aminobenzoate-N-D-xyloside,

2.4 parts by weight of a non-ionic surfactant and

97 parts by weight of physiological saline solution

were mixed under heating and then the mixture was sterilized to be aninjection.

EXAMPLE 6 (Production of p-aminobenzoic acid-N-D-xyloside and its sodiumsalt)

A mixture of 2.3 g of p-aminobenzoic acid, 2.5 g of D-xylose and 0.05 gof ammonium chloride was heated in 25 ml of ethanol under a refluxcondenser. After the reaction was over, crystals separated out when thereaction mixture was kept in a refrigerator. The crystals thus obtainedby filtering were washed with water, aqueous methanolic solution, andthen with a small amount of ether. The crystals recrystallized from 94%ethanol were colorless needles. Yield was 73.7%. In the case whereammonium sulfate was used for ammonium chloride, a similar result wasobtained.

Thus obtained p-aminobenzoic acid-N-D-xyloside was dissolved graduallyinto an aqueous 1% sodium hydroxide solution containing in total thecalculated amount of sodium hydroxide and after filtering, the solutionwas condensed under reduced pressure. The crystals which separated outby the addition of a large excess of acetone to the condensate weredehydrated and dried. Colorless crystals of sodium salt was obtained atthe yield of 100%. The totel yield from p-aminobenzoic acid was 73.7%.

What is claimed is:
 1. A method for the treatment of hypertension, whichcomprises administering to a mammal suffering from hypertension aneffective amount of a compound of the formula: ##STR3## wherein ¹ Rdenotes the residual group formed by removing OH at 1 position fromxylose, or a pharamceutically acceptable salt thereof.
 2. Apharmaceutical composition in dosage unit form which comprises a dosageeffective for the treatment of hypertension of a compound of theformula: ##STR4## wherein ¹ R denotes the residual group formed byremoving OH at 1 position from xylose, or a pharmaceutically acceptablesalt thereof.
 3. A pharmaceutical composition according to claim 2,wherein said compound is p-aminobenzoic acid-N-D-xyloside.
 4. Apharmaceutical composition according to claim 2, wherein said compoundis sodium p-aminobenzoate-N-D-xyloside.